tbuckley/cabot-search huggingface dataset:
Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation
Authors: Xia Lu, Boshen Yang, Ruiqiang Qi, Qifei Xie, Taixi Li, Jie Yang, Tingting Tong, Kaifan Niu, mingyu Li, Weijun Pan, Yongxin Zhang, Dongmei Shi, Suiji Li, Cuilian Dai, Chengxing Shen, Xiaoqing Wang, Yan Wang, Juan Song
Journal: Theranostics (2022)

Rationale: Previous studies have suggested that myocardial inflammation plays a critical role after ischemic myocardial infarction (MI); however, the underlying mechanisms still need to be fully elucidated. WW domain-containing ubiquitin E3 ligase 1 (WWP1) is considered as an important therapeutic target for cardiovascular diseases due to its crucial function in non-ischemic cardiomyopathy, though it remains unknown whether targeting WWP1 can alleviate myocardial inflammation and ischemic injury post-MI. Methods: Recombinant adeno-associated virus 9 (rAAV9)-cTnT-mediated WWP1 or Kruppel-like factor 15 (KLF15) gene transfer and a natural WWP1 inhibitor Indole-3-carbinol (I3C) were used to determine the WWP1 function in cardiomyocytes. Cardiac function, tissue injury, myocardial inflammation, and signaling changes in the left ventricular tissues were analyzed after MI. The mechanisms underlying WWP1 regulation of cardiomyocyte phenotypes in vitro were determined using the adenovirus system. Results: We found that WWP1 expression was up-regulated in cardiomyocytes located in the infarct border at the early phase of MI and in hypoxia-treated neonatal rat cardiac myocytes (NRCMs). Cardiomyocyte-specific WWP1 overexpression augmented cardiomyocyte apoptosis, increased infarct size and deteriorated cardiac function. In contrast, inhibition of WWP1 in cardiomyocytes mitigated MI-induced cardiac ischemic injury. Mechanistically, WWP1 triggered excessive cardiomyocyte inflammation after MI by targeting KLF15 to catalyze K48-linked polyubiquitination and degradation. Ultimately, WWP1-mediated degradation of KLF15 contributed to the up-regulation of p65 acetylation, and activated the inflammatory signaling of MAPK in ischemic myocardium and hypoxia-treated cardiomyocytes. Thus, targeting of WWP1 by I3C protected against cardiac dysfunction and remodeling after MI. Conclusions: Our study provides new insights into the previously unrecognized role of WWP1 in cardiomyocyte inflammation and progression of ischemic injury induced by MI. Our findings afford new therapeutic options for patients with ischemic cardiomyopathy.
Size-advantage of monovalent nanobodies against the macrophage mannose receptor for deep tumor penetration and tumor-associated macrophage targeting
Authors: Marco Erreni, Francesca D'Autilia, Roberta Avigni, Evangelia Bolli, Sana M. Arnouk, Kiavash Movahedi, Pieterjan Debie, Achille Anselmo, Raffaella Parente, Cécile Vincke, Fijs W.B. van Leeuwen, Paola Allavena, Cecilia Garlanda, Alberto Mantovani, Andrea Doni, Sophie Hernot, Jo A. Van Ginderachter
Journal: Theranostics (2022)

Rationale: Nanobodies (Nbs) have emerged as an elegant alternative to the use of conventional monoclonal antibodies in cancer therapy, but a detailed microscopic insight into the in vivo pharmacokinetics of different Nb formats in tumor-bearers is lacking. This is especially relevant for the recognition and targeting of pro-tumoral tumor-associated macrophages (TAMs), which may be located in less penetrable tumor regions. Methods: We employed anti-Macrophage Mannose Receptor (MMR) Nbs, in a monovalent (m) or bivalent (biv) format, to assess in vivo TAM targeting. Intravital and confocal microscopy were used to analyse the blood clearance rate and targeting kinetics of anti-MMR Nbs in tumor tissue, healthy muscle tissue and liver. Fluorescence Molecular Tomography was applied to confirm anti-MMR Nb accumulation in the primary tumor and in metastatic lesions. Results: Intravital microscopy demonstrated significant differences in the blood clearance rate and macrophage targeting kinetics of (m) and (biv)anti-MMR Nbs, both in tumoral and extra-tumoral tissue. Importantly, (m)anti-MMR Nbs are superior in reaching tissue macrophages, an advantage that is especially prominent in tumor tissue. The administration of a molar excess of unlabelled (biv)anti-MMR Nbs increased the (m)anti-MMR Nb bioavailability and impacted on its macrophage targeting kinetics, preventing their accumulation in extra-tumoral tissue (especially in the liver) but only partially influencing their interaction with TAMs. Finally, anti-MMR Nb administration not only allowed the visualization of TAMs in primary tumors, but also at a distant metastatic site. Conclusions: These data describe, for the first time, a microscopic analysis of (m) and (biv)anti-MMR Nb pharmacokinetics in tumor and healthy tissues. The concepts proposed in this study provide important knowledge for the future use of Nbs as diagnostic and therapeutic agents, especially for the targeting of tumor-infiltrating immune cells.
Intravital imaging and cavitation monitoring of antivascular ultrasound in tumor microvasculature
Authors: Xiaoxiao Zhao, Carly Pellow, David E. Goertz
Journal: Theranostics (2022)

Focused ultrasound-stimulated microbubbles have been shown to be capable of inducing blood flow shutdown and necrosis in a range of tissue types in an approach termed antivascular ultrasound or nonthermal ablation. In oncology, this approach has demonstrated tumor growth inhibition, and profound synergistic antitumor effects when combined with traditional platforms of chemo-, radiation- and immune-therapies. However, the exposure schemes employed have been broad and underlying mechanisms remain unclear with fundamental questions about exposures, vessel types and sizes involved, and the nature of bubble behaviors and their acoustic emissions resulting in vascular damage - impeding the establishment of standard protocols.
A labeling strategy for the three-dimensional recognition and analysis of microvascular obstruction in ischemic stroke
Authors: Yusha Li, Jianyi Xu, Tingting Yu, Jingtan Zhu, Ang Xuan, Xiaomei Liu, Pingfu Wang, Dongyu Li, Dan Zhu
Journal: Theranostics (2022)

Large vessel recanalization in ischemic stroke does not always go along with tissue reperfusion, a phenomenon called "no-reflow". However, knowledge of the mechanism of no-reflow is limited because identifying microvascular obstruction across the cortex and subcortex both in clinical and experimental models is challenging. In this study, we developed a smart three-dimensional recognition pipeline for microvascular obstruction during post-ischemia reperfusion to examine the underlying mechanism of no-reflow.
Artificial intelligence-based recognition for variant pathogenicity of BRCA1 using AlphaFold2-predicted structures
Authors: Chang Li, Lili Zhang, Zhongling Zhuo, Fei Su, Hexin Li, Siyuan Xu, Ye Liu, Zaifeng Zhang, Yibo Xie, Xue Yu, Liheng Bian, Fei Xiao
Journal: Theranostics (2022)

With the surge of the high-throughput sequencing technologies, many genetic variants have been identified in the past decade. The vast majority of these variants are defined as variants of uncertain significance (VUS), as their significance to the function or health of an organism is not known. It is urgently needed to develop intelligent models for the clinical interpretation of VUS. State-of-the-art artificial intelligence (AI)-based variant effect predictors only learn features from primary amino acid sequences, leaving out information about the most important three-dimensional structure that is more related to its function. Methods: We proposed a deep convolutional neural network model named variant effect recognition network for BRCA1 (vERnet-B) to recognize the clinical pathogenicity of missense single-nucleotide variants in the BRCT domain of BRCA1. vERnet-B learned features associated with the pathogenicity from the tertiary protein structures of variants predicted by AlphaFold2. Results: After performing a series of validation and analyses on vERnet-B, we discovered that it exhibited significant advances over previous works. Recognizing the phenotypic consequences of VUS is one of the most daunting challenges in genetic informatics; however, we achieved 85% accuracy in recognizing disease BRCA1 variants with an ideal balance of false-positive and true-positive detection rates. vERnet-B correctly recognized the pathogenicity of variant A1708E, which was poorly predicted by AlphaFold2 as previously described. The vERnet-B web server is freely available from URL: http://ai-lab.bjrz.org.cn/vERnet. Conclusions: We applied protein tertiary structures to successfully recognize the pathogenic missense SNVs, which were difficult to be addressed by classical approaches based on sequences. Our work demonstrated that AlphaFold2-predicted structures were expected to be used for rich feature learning and revealed unique insights into the clinical interpretation of VUS in disease-related genes, using vERnet-B as a discovery tool.
Multiple mitochondria-targeted components screened from Sini decoction improved cardiac energetics and mitochondrial dysfunction to attenuate doxorubicin-induced cardiomyopathy
Authors: Xin Ding, Ya Zhang, Pengchao Pan, Cuiping Long, Xingxing Zhang, Lingxin Zhuo, Qian Zhou, Wenting Liao, Guangguo Tan
Journal: Theranostics (2022)

Rationale: Sini decoction (SND) is an efficient formula against DOX-induced cardiomyopathy (DCM), but the active ingredient combination (AIC) and mechanisms of SND remain unclear.Therefore, the present study aimed to identify the AIC and elucidate the underlying mechanism of AIC on DCM.Methods: The AIC were screened by a novel comprehensive two-dimensional cardiac mitochondrial membrane chromatography (CMMC)-TOFMS analysis system and further validated by cell viability, reactive oxygen species (ROS) generation, ATP level, and mitochondrial membrane potential in DOX-induced H9c2 cell injury model.Then, an integrated model of cardiac mitochondrial metabolomics and proteomics were applied to clarify the underlying mechanism in vitro.Results: The CMMC column lifespan was significantly improved to more than 10 days.Songorine (S), neoline, talatizamine, 8-gingerol (G) and isoliquiritigenin (I), exhibiting stronger retention on the first-dimension CMMC column, were screened to have protective effects against DOX cardiotoxicity in the H9c2 cell model.S, G and I were selected as an AIC from SND according to the bioactivity evaluation and the compatibility theory of SND.The combined in vitro use of S, G and I produced more profound therapeutic effects than any component used individually on increasing ATP levels and mitochondrial membrane potential and suppressing intracellular ROS production.Moreover, SGI attenuated DCM might via regulating mitochondrial energy metabolism and mitochondrial dysfunction.Conclusions: The provided scientific evidence to support that SGI combination from SND could be used as a prebiotic agent for DCM.Importantly, the proposed two-dimensional CMMC-TOFMS analytical system provides a high-throughput screening strategy for mitochondria-targeted compounds from natural products, which could be applied to other subcellular organelle models for drug discovery.
Clinical Psychiatry. A Text-Book for Students and Physicians. Abstracted and Adapted from the Sixth German Edition of Kraepelin's "Lehrbuch der Psychiatrie."
Authors: A. Ross Diefendorf, Emil Kraepelin
Journal: JAMA (1902)

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STAT6 gain-of-function variant exacerbates multiple allergic symptoms
Authors: Ichiro Takeuchi, Kumiko Yanagi, Shuji Takada, Toru Uchiyama, Arisa Igarashi, Kenichiro Motomura, Yuka Hayashi, Naoko Nagano, Ryo Matsuoka, Hiroki Sugiyama, Takako Yoshioka, Hirohisa Saito, Toshinao Kawai, Yumiko Miyaji, Yusuke Inuzuka, Yoichi Matsubara, Yukihiro Ohya, Toshiaki Shimizu, Kenji Matsumoto, Katsuhiro Arai, Ichiro Nomura, Tadashi Kaname, Hideaki Morita
Journal: Journal of Allergy and Clinical Immunology (2022)
Exon Elongation Added Intrinsically Disordered Regions to the Encoded Proteins and Facilitated the Emergence of the Last Eukaryotic Common Ancestor
Authors: Satoshi Fukuchi, Tamotsu Noguchi, Hiroto Anbo, Keiichi Homma
Journal: Molecular Biology and Evolution (2022)

Abstract Most prokaryotic proteins consist of a single structural domain (SD) with little intrinsically disordered regions (IDRs) that by themselves do not adopt stable structures, whereas the typical eukaryotic protein comprises multiple SDs and IDRs. How eukaryotic proteins evolved to differ from prokaryotic proteins has not been fully elucidated. Here, we found that the longer the internal exons are, the more frequently they encode IDRs in eight eukaryotes including vertebrates, invertebrates, a fungus, and plants. Based on this observation, we propose the “small bang” model from the proteomic viewpoint: the protoeukaryotic genes had no introns and mostly encoded one SD each, but a majority of them were subsequently divided into multiple exons (step 1). Many exons unconstrained by SDs elongated to encode IDRs (step 2). The elongated exons encoding IDRs frequently facilitated the acquisition of multiple SDs to make the last common ancestor of eukaryotes (step 3). One prediction of the model is that long internal exons are mostly unconstrained exons. Analytical results of the eight eukaryotes are consistent with this prediction. In support of the model, we identified cases of internal exons that elongated after the rat–mouse divergence and discovered that the expanded sections are mostly in unconstrained exons and preferentially encode IDRs. The model also predicts that SDs followed by long internal exons tend to have other SDs downstream. This prediction was also verified in all the eukaryotic species analyzed. Our model accounts for the dichotomy between prokaryotic and eukaryotic proteins and proposes a selective advantage conferred by IDRs.
Chronic Obstructive Pulmonary Disease Mortality by Industry and Occupation — United States, 2020
Authors: Girija Syamlal, Laura M. Kurth, Katelynn E. Dodd, David J. Blackley, Noemi B. Hall, Jacek M. Mazurek
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Chronic obstructive pulmonary disease (COPD), a progressive lung disease, is characterized by long-term respiratory symptoms and airflow limitation (1). COPD accounts for most of the deaths from chronic lower respiratory diseases, the sixth leading cause of death in the United States in 2020.* Workplace exposures and tobacco smoking are risk factors for COPD; however, one in four workers with COPD have never smoked (2-4). To describe COPD mortality among U.S. residents aged ≥15 years categorized as ever-employed (i.e., with information on their usual industry and occupation), CDC analyzed the most recent 2020 multiple cause-of-death data† from 46 states and New York City.§ Among 3,077,127 decedents, 316,023 (10.3%) had COPD¶ listed on the death certificate. The highest age-adjusted** COPD death rates per 100,000 ever-employed persons were for females (101.3), White persons (116.9), and non-Hispanic or Latino (non-Hispanic) persons (115.8). The highest proportionate mortality ratios (PMRs)†† were for workers employed in the mining industry (1.3) and in food preparation and serving related occupations (1.3). Elevated COPD mortality among workers in certain industries and occupations underscores the importance of targeted interventions (e.g., reduction or elimination of COPD-associated risk factors, engineering controls, and workplace smoke-free policies) to prevent COPD from developing and to intervene before illness becomes symptomatic or severe.
Progress Toward Poliomyelitis Eradication ― Afghanistan, January 2021–September 2022
Authors: Abdinoor Mohamed, Irfan Elahi Akbar, Sumangala Chaudhury, Mufti Zubair Wadood, Fazal Ather, Jaume Jorba, Maureen Martinez
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Afghanistan and Pakistan are the two remaining countries with endemic wild poliovirus type 1 (WPV1) transmission (1). During 2019-2020, these countries reported their highest numbers of WPV1 cases since 2014 and experienced outbreaks of type 2 circulating vaccine-derived poliovirus (cVDPV2) (2-4).* In Afghanistan, the number of WPV1 cases nearly doubled, from 29 in 2019 to 56 in 2020; 308 cVDPV2 cases were reported during 2020. After years of active conflict, the Afghanistan government was fully replaced by the Taliban de facto government on August 15, 2021. This report describes activities and progress toward polio eradication in Afghanistan during January 2021-September 2022 and updates previous reports (3,4). During January-December 2021, four WPV1 and 43 cVDPV2 cases were detected, representing decreases of 93% from 56 cases and 86% from 308 cases, respectively, during 2020. During January-September 2022 (reported as of October 20), two WPV1 cases and zero cVDPV2 cases were detected. Although no supplementary immunization activities (SIAs)† occurred during July-October 2021, SIAs resumed during November 2021 in all districts after the political transition, and 3.5-4.5 million previously unreachable persons have been vaccinated since. However, restrictions on how SIAs are conducted are still in place in the critical South Region provinces of Kandahar, Helmand, and Uruzgan. If efforts to vaccinate all children are enhanced and expanded, Afghanistan has an opportunity to interrupt WPV1 transmission during 2023.
<i>QuickStats:</i> Percentage* of Office-Based Physicians Using Telemedicine Technology,† by Specialty§ — United States, 2019 and 2021
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Total (all specialties)Primary care Surgical specialty Medical specialty PercentageOffice-based physicians, by specialty 2021 2019 * With 95% CIs indicated by error bars.† Telemedicine technology was defined as the use of audio with video or web videoconference for patient visits.§ Primary care physicians are defined as physicians in the following specialties: general and family practice, internal medicine, obstetrics and gynecology, and pediatrics.Surgical specialty physicians are defined as physicians in general surgery, obstetrics and gynecology surgery, ophthalmology, orthopedic surgery, other, otolaryngology, and urology.Medical specialty physicians are defined as physicians in cardiovascular diseases, dermatology, neurology, other, and psychiatry.From 2019 to 2021, the use of telemedicine technology increased for office-based physicians from 15.4% to 85.9%.In both 2019 and 2021, the use of telemedicine technology was higher among primary care physicians and medical specialty physicians than it was among surgical specialty physicians.In 2021, 91.4% of primary care physicians, 87.2% of medical specialty physicians, and 74.8% of surgical specialty physicians used telemedicine technology.
Human Rabies — Texas, 2021
Authors: Dawn Blackburn, Faisal S. Minhaj, Roukaya Al Hammoud, Lillian Orciari, Jael Miller, Trevor Maness, Jon Stewart, Brittany Singletary, Elvia Ledezma, Misti Ellsworth, Andrea Carlo-Angleró, Michael Niezgoda, Crystal M. Gigante, Agam K. Rao, Panayampalli S. Satheshkumar, Gloria P. Heresi, Amanda Kieffer, Ryan M. Wallace
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

In late August 2021, a boy aged 7 years was bitten by a bat while he was playing outside his apartment home in Medina County, Texas. He informed his parents; however, no rabies postexposure prophylaxis (PEP) was sought because there were no visible bite marks, and the family was unaware that contact with a bat, including in the absence of visible bite marks, might cause rabies. Approximately 2 months later, the child was hospitalized for altered mental status, seizures, and hypersalivation and ultimately received a diagnosis of rabies. Experimental therapies were attempted; however, the child died 22 days after symptom onset. Fifty-seven persons who met criteria for suspected or known exposure to infectious secretions in this case were advised to consult with a medical provider about the need for rabies PEP in accordance with Advisory Committee on Immunization Practices (ACIP) guidelines (1). Rabies, an acute, progressive neuroencephalitis, is nearly always fatal. Although dogs are the most common source of human rabies deaths worldwide and account for an estimated 59,000 annual cases of human rabies globally (2), bats are the most common source of domestically acquired rabies in the United States and have been implicated in 31 (81.6%) of 38 human infections since 2000 (3). Attempts to prevent death or poor neurologic outcomes once rabies symptoms develop have been largely unsuccessful (4). Administration of rabies PEP, comprising rabies immunoglobulin and a series of doses of rabies vaccine, is critical to preventing rabies after an exposure; enhanced public education about the risk posed by bats, and the availability of PEP to prevent rabies, is needed.